Describe the structure of the steroid nucleus.
Four fused carbon rings: three 6-carbon rings and a 5-carbon ring.
Cholesterol esterified with long chain fatty acid. The LCFA is connected through the hydroxyl group on ring A.
Cholesterol is present in plasma in what form?
30% of total plasma cholesterol is free cholesterol. It is also present esterified with lipoproteins.
What are the sources of acetyl-CoA?
beta-oxidation of fatty acids, oxidation of amino acids, and pyruvate dehydrogenase reaction
What is the rate-limiting step of cholesterol biosynthesis?
Conversion of HMG-CoA to Mevalonate by HMG-CoA reductase. The reaction requires 2 NADPH + H, which are oxidized to NADP+.
Where is HMG-CoA reductase located? Where does the reaction occur?
Located in the ER, but reaction occurs in the cytosol.
What is isoprene?
2-methyl-1-butylene. It is usually in its active form, which has pyrophosphate attached to C4.
How many carbons does squalene have? How many isoprene units is it made up of?
30 carbons, 6 isoprene units
What are some byproducts of cholesterol biosynthesis (5)?
Geranylgeranylated proteins, dolichol, ubiquinone, farnesylated proteins, Heme A
Addition of activated isoprenyl units realeases what molecule? What effect does this have on the reaction?
Pyrophosphate is cleaved, making the reaction irreversible.
Several intermediates in the production of squalene can be used for other things. What are the two substrates for prenylation enzymes? What is their precursor?
FPP and GGPP, which are derived from mevalonate.
Several intermediates in the production of squalene can be used for other things. FPP gives rise to what types of proteins? Give an example.
Farnesylated small G proteins like Ras, GGPP, Squalene, and Heme A.
Several intermediates in the production of squalene can be used for other things. GGPP gives rise to what types of proteins? Give examples.
Geranylgeranylated small G proteins like Rho Rac, and Cdc42. It also gives rise to Rab small G proteins, dolichol, and ubiquinone.
What are the last steps of cholesterol synthesis?
Ring closure converts Squalene into the steroid nucleus, Lanosterol. Cholesterol is derived from lanosterol and further processed into other things.
Where is cholesterol synthesized? What organ synthesizes the most? The least?
Basically everywhere, but especially in the liver, intestine, adrenal cortex, and reproductive tissues. The liver synthesizes the most. The adrenal medulla synthesizes the least.
How much cholesterol is excreted per day?
About 1g. Half in the feces as bile acids, half as cholesterol.
What factors increase intracellular free cholesterol concentration? (4)
De novo biosynthesis, dietary uptake, hydrolysis of intracellular cholesteryl esters, and receptor-mediated uptake of cholesterol-containing lipoproteins (LDL or scavenger receptors)
What factors decrease intracellular free cholesterol concentration?
Inhibition of cholesterol biosynthesis, down-regulation of the LDL receptor, intracellular esterification of cholesterol, conversion of cholesterol to bile acids or steroid hormones, transfer of membrane cholesterol to HDL, and regulation of HMG-CoA reductase.
What enzyme is responsible for intracellular esterification of cholesterol?
Acyl-CoA:cholesterol acyl transferase (ACAT)
What enzymes are responsible for efflux of cholesterol from the membrane to HDL?
ATP-binding cassette transporter A1 (ABCA-1) or class B scavenger receptor B1 (SR-B1)
How is HMG-CoA reductase regulated by drugs?
Statins are drugs which serves as analogs and reversible, competitive inhibitors of HMG-CoA reductase.
How is HMG-CoA reductase regulated by the cell?
Sterol-dependent regulation: SREBP binds to DNA at the SRE (sterol regulatory element).
Sterol-independent regulation: Activated by phosphoprotein phosphatase (insulin, thyroid hormone), inactivated by protein kinase (glucagon, glucocorticoids).
How is the intracellular cholesterol level managed by the cell?
Cholesterol esters in the diet are hydrolyzed to free cholesterol and absorbed in the intestine with dietary free cholesterol. This cholesterol, along with cholesterol synthesized by the intestines is transported in the blood by chylomicrons.
What effect does cholesterol have on ACAT?
Cholesterol is an allosteric activator of acyl-coenzyme A:cholesterol acyl transferase. It increases the esterifcation of cholesterol and fatty acids.
What is sodium stearate?
Quizlet says: A soap used in glycerin gelatin suppositories as a solidifying agent.
How are bile salts different from cholesterol?
Bile acids are synthesized in the liver by a multistep, multi-organelle pathway in which hydroxyl groups are inserted on the steroid structure, the double bond in ring B is reduced, and the hydrocarbon chain is shortened by three carbons with the introduction of a carboxyl group at the end of the chain.
Cholic acid is a (di/tri)ol. Chenodeoxycholic acid is a (di/tri)ol.
Cholic acid is a triol. Chenodeoxycholic acid is a diol.
What enzyme catalyzes the rate-limiting step for bile acid synthesis? How is it regulated?
Cholesterol-7-alpha-hydroxylase. Vitamin C is a cofactor. It is activated by cholesterol and down-regulated by cholic acid.
How are primary bile acids converted to bile salts?
They are conjugated with glycine or taurine (an end product of cysteine metabolism) by an amide bond between the carboxyl group of the bile acid and the amino group of the added compound.
What are the four major bile salts?
Glycocholic and glycochenodeoxycholic acids, and taurocholic and taurochenodeoxycholic acids.
Which bile salts are found in highest concentration?
Glycine forms (glycocholic and glycochenodeoxycholic acids)
Where are secondary bile acids produced, and how?
Produced in the intestine by bacteria which remove a hydroxyl group from cholic acid or chenodeoxycholic acid.
What do bile salts/acids do in the intestine?
Bile salts provide the only significant mechanism for cholesterol excretion, both as a metabolic product of cholesterol and as an essential solubilizer for cholesterol excretion in bile. Bile acids act as detergents to assist the emulsification of ingested lipids into small globules.
Describe enterohepatic circulation.
Bile salts excreted into the intestine are reabsorbed and reused. They are primarily absorbed in the ileum and actively transported into the portal blood. They are then picked up by liver parenchymal cells. Bile acids are hydrophobic and are transported in blood by albumin. The liver converts any bile acids in the bile salt/acid mixture to bile salts which a re-excreted into the intestines.
How can bile salt excretion be promoted?
Bile acid sequestrants, such as cholestyramine, bind bile acids in the gut and prevent their reabsorption. Dietary fiber also binds bile acids and increases their excretion.
Which bile acid is not absorbed in the ileum and returned to the liver via enterohepatic circulation?
How are gallstones formed?
Primary bile acids are secreted into the duodenum or stored in the gall bladder as bile salts. When the cholesterol/bile acid ratio in the gallbladder is altered, the cholesterol cannot be solubilized by bile salts and lecithin. Cholesterol precipitates and combines with calcium to form gallstones.
Gallstone formation is promoted by what extrinsic factors?
Inactivity (non-stirred supersaturated solution of cholesterol) and fasting (lack of periodic expulsion and replenishment of bile)
Not all patients with cholelithiasis are candidates for gallbladder removal surgery. What treatment options are available for these patients?
Administration of chenodeoxycholic acid supplements the body's supply of bile acids and results in a very gradual dissolution of gallstones.
What is the precursor for Vitamin D3? How is it converted to Vitamin D3?
Cholesterol; 7-dehydrocholesterol is converted to provitamin D3 by UV photolysis. Provitamin D3 is then converted to vitamin D3.
Cholesterol can be converted to several different steroid hormones. What are 6 of them?
Pregnenolone, progesterone, cortisol, aldosterone, testosterone, and estradiol
Bile acids/salts can activate some receptors. What are two of them? And what are they for?
Farnesoid X receptors and activated G protein-coupled receptor TGR5. These receptors help regulate lipid, glucose, and energy metabolism.
What do atherosclerotic plaques contain?
Cholesterol, cholesteryl esters, collagen, proteoglycan, and elastin.
What kind of LDL:HDL cholesterol ratio would be a positive indicator of atherosclerosis?
High LDL, low HDL promotes atherosclerosis. High HDL transports cholesterol for excretion, decreasing the risk of atherosclerosis.